Exploration of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides as potent, orally active Factor Xa inhibitors with extended duration of action.

Autor: Van Huis CA; Michigan Laboratories, Ann Arbor Campus, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA., Casimiro-Garcia A, Bigge CF, Cody WL, Dudley DA, Filipski KJ, Heemstra RJ, Kohrt JT, Leadley RJ Jr, Narasimhan LS, McClanahan T, Mochalkin I, Pamment M, Peterson JT, Sahasrabudhe V, Schaum RP, Edmunds JJ
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2009 Mar 15; Vol. 17 (6), pp. 2501-11. Date of Electronic Publication: 2009 Feb 03.
DOI: 10.1016/j.bmc.2009.01.063
Abstrakt: Aiming to improve upon previously disclosed Factor Xa inhibitors, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored with the intent of increasing the projected human half-life versus 5 (projected human t(1/2)=6 h). A stereospecific route to compounds containing a 4-aryl-4-hydroxypyrrolidine scaffold was developed, resulting in several compounds that demonstrated an increase in the half-life as well as an increase in the in vitro potency compared to 5. Reported herein is the discovery of 26, containing a (2R,4S)-4-hydroxy-4-(2,4-difluorophenyl)-pyrrolidine scaffold, which is a selective, orally bioavailable, efficacious Factor Xa inhibitor that appears suitable for a once-daily dosing (projected human t(1/2)=23 h).
Databáze: MEDLINE
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